Lab Notes: Test Access Trumps Test Accuracy

The best diagnostic test methodology in the world is useless if patients reject it or can't afford it. Also this week: tPA may not need to bust blood clots to protect against stroke damage.

Diagnostic Test Access May Trump Accuracy

A modestly accurate diagnostic test for Alzheimer's disease that patients can and will use would be better for public health than one that's difficult to obtain but has superior technical specs, a computer simulation suggested.

The most accurate tests for Alzheimer's disease developed so far rely either on lumbar punctures or expensive PET scans. When tests are painfully invasive or unaffordable, patients will tend to avoid them. In the case of Alzheimer's disease, that would typically mean that patients would then go untreated.

Researchers from Bristol-Myers Squibb and Yale University ran computer models to estimate the effect on Alzheimer's treatment given various assumptions about the uptake and diagnostic accuracy of hypothetical tests.

The results, presented in a poster at the Alzheimer's Association International Conference this week, indicated that more patients would receive proper treatment with a test of medium accuracy and low access problems, compared with a highly accurate test that fewer patients actually receive.

"A test that is highly sensitive and specific, yet has significant barriers to patient access, will not facilitate identifying the 'right' patients for treatment and may become a significant obstacle to appropriate care," the researchers concluded.

-- John Gever

Defanged tPA May Still Protect the Brain

Tissue plasminogen activator (tPA) may protect against the ravages of stroke through mechanisms separate from its clot-dissolving abilities, a study in the Journal of Neuroscience showed.

Manuel Yepes, MD, of Emory University in Atlanta, and colleagues explored the other functions of the drug in cultured neurons from the cerebral cortex. They showed that even when the drug was modified so it no longer converted plasminogen to plasmin, it protected cultured neurons from the stroke-related loss of oxygen and glucose by activating a pathway that helps cells withstand the insult.

When the researchers gave a form of tPA that did not have clot-busting abilities to mice with an induced stroke, they found that the drug still reduced the infarct size.

The experiments also showed that the protective effect could be achieved at lower doses than given in cases of acute stroke, which could have implications for designing a new therapy that does not carry an increased risk of bleeding.

"The risk of bleeding creates a lot of anxiety, and it has resulted in the regrettable fact that only a small number of stroke patients currently benefit from treatment with tPA," Yepes said in a statement.

-- Todd Neale

Axon Protein May Be Key in Fighting Neurodegeneration

The multifunctional protein spectraplakin -- which helps stabilize axon grown -- may be a focus of future research on brain disorders, according to another report in The Journal of Neuroscience.

The researchers studied how actin and microtubule proteins combine to form a cell's cytoskeleton in fruit flies, and what role spectraplakins play in the cytoskeletal development. They were able to replicate their findings in mouse studies, suggesting possible clinical application in humans.

The team found that spectraplakins link the actin and microtubules and that, absent the bond, the microtubules will not arrange properly, leading to hindered axon growth.

"Understanding cytoskeletal machinery at the cell level is a holy grail of current cell research that will have powerful clinical applications. Thus, cytoskeleton is crucially involved in virtually all aspects of a cell's life," said study co-author Andreas Prokop, PhD, of the University of Manchester in England.

He added,"Deciphering the principles of cytoskeletal machinery during the fundamental process of axon growth will essentially help research into the causes of a broad spectrum of diseases."

-- Cole Petrochko

Stress Paves the Way for Bone Metastasis

For women with breast cancer, stress and depression may boost their risk of metastasis to bone, a mouse study suggested.

Activation of the sympathetic nervous system -- "one of many pathophysiological consequences of severe stress and depression" -- primed the bone microenvironment for colonization by breast cancer cells, researchers reported in PLoS Biology.

Mice given a drug that mimics sympathetic nervous system activation developed more cancer lesions in bone, as did mice stressed out by being put in restraints. But treating the mice with the blood pressure-lowering drug propranolol had the opposite effect, blocking bone metastasis.

"If something as simple as a beta-blocker could prevent cancer metastasis to bone, this would impact the treatment of millions of patients worldwide," lead author Florent Elefteriou, PhD, of Vanderbilt University in Nashville, noted in a press release.

The research also showed that the process depends on RANK ligand signaling, which plays a role in bone breakdown as well as cell migration.

That suggests that drugs interfering with this signaling, like denosumab (Xgeva), "could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the 'vicious cycle' of bone destruction induced by these cells," the group concluded.

-- Crystal Phend

Oxidative Stress Impairs Immune Function

As cells age, they spit out more reactive oxygen species – aka free radicals – while producing fewer enzymes that can remove these potentially harmful compounds, leading to a chronic state of oxidative stress.

Now, researchers at the Albert Einstein College of Medicine in Bronx, N.Y., have directly observed that process in immune cells – potentially explaining why older patients have reduced immunity.

Laura Santambrogio, MD, PhD, and colleagues looked specifically at dendritic cells, the immune system's front-line defenders, in aging mice and found that oxidatively modified proteins had accumulated in those cells.

This particularly hampered the function of endosomes, providing evidence that age-related oxidative stress interferes with the ability to mount an immune response.

Indeed, when the researchers gave mice an antioxidant every day for two weeks, some of the effects of oxidative stress were reversed, they reported in Cell.

"Many elderly people respond very poorly to vaccination, so perhaps a cycle of therapy with antioxidants before vaccination might improve their immune response to vaccines," Santambrogio said in a statement.

-- Kristina Fiore

HIV Protein Linked to Dementia

People with HIV-associated dementia have higher levels of a protein than destroys neurons than either healthy people or HIV-positive people without dementia, according to researchers led by Italo Mocchetti, PhD, of Georgetown University Medical Center in Washington, D.C. And a series of in vitro experiments suggests that is because HIV itself helps maintain high levels of pro–brain-derived neurotrophic factor (or proBDNF), which is toxic to neurons.

In culture, the HIV surface protein gp120 produces accumulation of proBDNF and a decrease in the mature protein BDNF, which promotes neuronal growth, Mocchetti and colleagues reported in the Journal of Neuroscience. Analysis suggested that gp120 decreases the intracellular level of furin, which cleaves proBDNF to make the mature protein.

The finding could lead to new therapies for HIV-associated dementia that would increase levels of mature BDNF, the researchers argued.

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